Biocompatible polymeric materials have been used extensively in medical implant devices. For some applications (e.g., bone fixtures, sutures, drug containing implants etc.), the polymers should be not only biocompatible, but also degradable into non-toxic products. This degradability eliminates the need to remove later the device from the implant site.
The first degradable polymers were based on hydrophobic polymers like PLGA, poly(orthoesters), polyanhydrides and polyiminocarbonates, which degrade hydrolytically into water-soluble monomers and oligomers. The degradation times of these polymers are a function of their chemical composition. The problem with these polymers is the need to keep them completely dry during storage. Additionally, the majority of degradable polymers are essentially hard, brittle materials, developed for drug delivery uses.
Other degradable polymers are based on naturally-occurring polymers, e.g., polysaccharides or polypeptides. The degradation process is based on enzymatic hydrolysis of the polysaccharides or polypeptides. While these products can be formed as hydrogels, and therefore may be stored in an aqueous environment, the degradation time is not controllable due to variable enzyme expression in humans. Additionally, only the unmodified part of the protein or polysaccharide is degradable, while modified sites are not degradable. Furthermore, naturally-derived products have to undergo vigorous testing to ensure that they are free of endotoxins and contaminating proteins. For human- or animal-derived proteins, viral contamination is a constant worry.
Another approach to degradability is to synthesize a hydrogel containing an unstable crosslinker. This approach has been investigated by a number of groups. The first approach was to polymerize the hydrogel in situ using photopolymerization of monomers that contain a hydrolytically labile lactic acid component. The degradation time can be adjusted through the number of lactic acid units incorporated into the monomer. However, prior to polymerization, these monomers must be stored under anhydrous conditions.
Another approach has been to synthesize crosslinkers containing hydrolytically labile carbonate (Bruining et al, Biomaterials 21 (2000) 595-604), ester (Argade et al, Polymer Bulletin 31 (1993) 401-407), or phosphazene linkers (Grosse-Sommer et al, Journal of Controlled Release 40 (1996) 261-267). These hydrogels are not stable under any of the conditions described and begin to degrade immediately following synthesis and exposure to an aqueous environment. Yet another approach utilizes a reduction/oxidation cleavable crosslinker, such as a disulfide bridge. However, the reduction product from the disulfide bridge is two thiols, which are easily reoxidized to the disulfide bridge, thereby restoring the crosslink.
Still another approach would use a crosslinker that is stable under either basic or acidic conditions, and starts to degrade at blood pH, roughly 7.4. Ruckenstein et al (Ruckenstein et al, Macromolecules, 32 (1999) 3979-3983; U.S. Pat. No. 6,323,360) described one such crosslinker as the addition product between ethylene glycol divinyl ether and methacrylic acid. The resulting crosslinker, containing hemiacetal functional groups, is base stable and degrades under acidic conditions. However, the publication does not provide a means to control the degradation time, nor are the described degradation conditions in organic solvents meaningful for biological applications.
Another degradable crosslinker has been described by Ulbrich (Ulbrich et al, Journal of Controlled Release, 24 (1993) 181-190; Ulbrich et al, Journal of Controlled Release, 34 (1995) 155-165; U.S. Pat. No. 5,130,479; U.S. Pat. No. 5,124,421). The crosslinker is N,O-dimethacryloylhydroxylamine. The degradation of this crosslinker is based on the base-catalyzed Lossen rearrangement of substituted hydroxamic acids. The crosslinker appears to be stable under acidic conditions, while degradation occurs at neutral to basic pH. The only way disclosed by Ulbrich et al to control degradation is through the crosslink density. Increasing the crosslink density from 1.2% to 2.4% increases the degradation time from 21 hours to 45 hours at pH 7.4 (U.S. Pat. No. 5,124,421). Akala (Akala, Pharm Pharmacol Lett 8 (1998) 129-132) discovered that the introduction of acrylic acid groups into a linear polymer accelerated the degradation of the pendant N, O-diacylhydroxyamine moieties, an effect not reported by Ulbrich et al.